Regulating genes and neurons in brains

Fruit flies have tiny brains about a quarter of a centimetre in width and can be seen without a microscope. Andrea Brand is looking for stem cells in adult fruit flies' brains and trying to understand how genes are regulated throughout life. The aim of the work is to learn how to control cells to produce the right neuron at the right place at the right time. One protein, known by the name Prospero, is responsible for regulating stem cells to produce cells which produce neurons. Without the Prospero protein, tumours result.

Transcript

Robyn Williams: And so from very big animals to the very small. Before we go to Cambridge to meet them some thoughts from Prospero in The Tempest.

Gentle breath of yours my sails must fill, or else my project fails,which was to please. Now I want spirits to enforce, art to enchant,and my ending in despair,unless I be relieved by prayer,which pierces so that it assaults mercy itself and frees all faults.

Robyn Williams: Prospero's speech, or part of it, with John Gielgud, all to introduce some tiny fruit flies with even tinier brains. You'll see the connection later. And the Herchel Smith Professor of Neurology at Cambridge, Andrea Brand, with some very exciting work.

Andrea Brand: Absolutely, yes. Actually the brain develops in the embryo and continues to develop through larval life until it develops into an adult brain and you have a walking, flying, behaving adult.

Robyn Williams: How big is the brain in this little creature?

Andrea Brand: Ooh, quite tiny actually. Well we do everything under microscopes because we dissect the brains out. I mean the cells we look at are about 10 microns across, and the brain's, well maybe half a centimetre, if not smaller, a quarter of a centimetre.

Robyn Williams: Oh well that's quite respectable really, isn't it?

Andrea Brand: Yes, you can see them without a microscope, but if you want to look at them in any detail we use microscopes to make them bigger.

Robyn Williams: And so when you're investigating and looking into them how are you teasing them out to see how they function?

Andrea Brand: Well, we do several things. Ideally it's nice to look at the brain in the living animal, but for certain things we actually dissect the brains out and we can look at individual cells by labeling them with antibodies or dyes or with green fluorescent protein.

Robyn Williams: And do you find stem cells within them ready made?

Andrea Brand: Yes, there are stem cells in the brains of these flies, and in particular we're looking at the embryo in the larva.

Robyn Williams: I see. Well you'd expect stem cells to be there but you wouldn't necessarily see them when they're adult or would you? Are brain cells replaced as you age?

Andrea Brand: Well this is a terrific question. If you look at the published literature people have not found stem cells in the brains of adult Drosophila, but that's what we're looking for now, and there certainly are stem cells in the embryo and in the larva, and I believe they're there in the adult too but we're trying to find them.

Robyn Williams: And how would you recognise them, they're quite different?

Andrea Brand: Well we're looking for cells that continue to divide, albeit it's rarely, and that will produce new neurons in the adult fly.

Robyn Williams: Well we know that adult human brains have got these cells being replaced. If they didn't someone like me would be a 'veg' long ago. So we're quite lucky that that continues. In a creature with a short lifespan, on the other hand, you wouldn't expect it, would you?

Andrea Brand: Well that's a question that I'd like to find out. I think we will find them even though the flies have a shorter lifespan, and perhaps maybe not as many, and perhaps only in particular regions of the brain. I think we probably will find them.

Robyn Williams: Yes. What happens when you put stem cells into a brain? Have you done it with the fruit fly?

Andrea Brand: We haven't put stem cells into the adult brain. You can certainly transplant stem cells in the embryo from one embryo to another, or from one region of the embryo to another, but we haven't done that ourselves, that's something that other labs have done.

Robyn Williams: There has been some discussion of course with human beings of putting stem cells into the brain to repair things and to help to rewire them. The only problem is sometimes they form tumours.

Andrea Brand: That's right. Well the regulation, and this is something that we're very interested in is stem cells have the capacity to self-renew. So when they divide they recreate themselves and they create another cell which goes on to produce neurons, and that regulation is extremely important. And we have shown that certain mutations which prevent the cells from producing neurons cause the stem cells to keep dividing and they form tumours even in the embryo. So in terms of therapy the ideal scenario would be to be able to regulate the stem cells that are already there to produce neurons that might need to be replaced, rather than introducing a stem cell from elsewhere. But that's probably going to take more time to accomplish.

Robyn Williams: Yeah, I don't know whether this is something of a diversion for you but I know the people who have tried to put stem cells into the heart found okay they do sit in the heart and they do live on but they don't change into cardiac cells. They just stay stem cells so they're not in fact repairing the heart at all, they're just sitting there.

Andrea Brand: Well again the cells need to receive signals from surrounding cells and some of those signals are specific for particular time points of development. And until we understand all the cell-cell interactions and the signals that the stem cell has to receive we can't get them to behave the way we want them to behave, and so what we need to understand is what are the signals that are required and how the stem cell will respond to those signals under different conditions.

Robyn Williams: Yes, so that you can tweak the stem cells and make them behave and do what you want.

Andrea Brand: Exactly, yes.

Robyn Williams: Yes. So where is your research leading now having set out on this quest? You've got the technology so you can look into the brain of the fruit fly so it can help you and you're in search of the stem cells. What next?

Andrea Brand: Well what we're trying to establish is that we'd like to look at what genes get turned on or off as these stem cells go through their life, and with the whole genome being sequenced we can now assess every gene in the genome and see whether it's on or off at a particular time. And what we've been developing is trying to isolate are single cells, or small groups of cells, from the brains and the nervous system and assess all the genes that are turned on or off at that particular time, and this is a way of getting at understanding what gene expression patterns are required for the stem cell to produce the right progeny, to keep dividing, to divide at the right time and not produce tumours.

Robyn Williams: I see, so it'd be like having the computer button, you press go on the genetic switch and it goes off and turns the stem cell into the neuronal cell that you require to help the brain work.

Andrea Brand: Exactly, yes. And if we can regulate that at the right time then we can produce the right sort of neuron in the right place at the right time. That's what we're aiming for.

Robyn Williams: Yes. What are the switches that you use, are they drugs that turn on particular parts of the DNA?

Andrea Brand: No, so what we found, we've been working a protein called Prospero, it's named after the Wizard in the The Tempest who controls the fates of the other characters.

Robyn Williams: As played by John Gielgud I seem to remember.

Andrea Brand: Yes. And the wonderful thing about Prospero is that it seems to be one of the proteins that's responsible for getting the stem cell to produce another cell that will give neurons. So if you remove Prospero what happens is that the cell that would normally give neurons also behaves as a stem cell and keeps dividing and leads to a tumour. So it seems to be a protein that, it's a transcription factor, so it regulates other genes and it's one of the factors that turns on the genes that are required for the neuron to be made, and without it you can't get these neurons made and you get tumours instead. So what we've done is to look at what genes Prospero regulates and see which genes it turns on and which genes it turns off, and we think that's one of the first steps in making the right sort of neuron in the animal.

Robyn Williams: I can actually see a wonderful time, five, 10 years ahead when we've got all these neuronal problems we want to fix, maybe lesions of the central nervous system, the spinal chord, who knows, and you play the genetic system switching it on and off and with stem cells that you infuse, just like in science fiction the rewiring takes place. Is that too outrageous a suggestion?

Andrea Brand: No, not necessarily. One of the other things was something that I developed when I was a postdoc at Harvard with Norbert Perrimon was a system called the GAL4 system which enables you to turn on genes at will in particular cells at particular times. And so once we know enough about which genes need to be on or off we can then use this system to turn those genes on or off in the right cells and see whether we can get the appropriate neuron at the appropriate time.

Robyn Williams: It's a very exciting prospect, isn't it?

Andrea Brand: Yes, I think so.

Robyn Williams: The brilliant Professor Andrea Brand in Cambridge whose husband by the way is also pretty smart, Jim Hasselhoff, ex-CSIRO who helped develop 'gene-shears' here.